Although vaccines to treat nicotine and cocaine addiction are currently in clinical trials, no specific medications exist to treat dependence on (+)-methamphetamine ((+)METH)-like drugs. To address this need, these preclinical studies will facilitate the medical discovery and development of new (+)METH- conjugate vaccines (MCVs) to help patients stop using (+)METH-like drugs. These important new MCVs are expected to block or reduce (+)METH effects in patients. The discovery of medically effective MCVs will be accomplished through our well-integrated, multidisciplinary research program designed to manufacture and test MCVs. In previous preclinical studies, our group showed that 1) titer and affinity of antibodies generated against MCV are not adversely affected by continuous (+)METH use, 2) a single MCV might be used to generate high-affinity antibodies against (+)METH and (+)-amphetamine ((+)AMP), and 3) anti-(+)METH monoclonal antibodies generated from a novel MCV can be used to reduce brain (+)METH concentrations and reduce (+)METH or (+)AMP self-administration. These accomplishments substantially enhanced our scientific vision, clearly defined the project's research aims, and identified a premier MCV candidate for the for use in active immunization. Our ultimate goal is to have one or more safe, effective MCV in a human- compatible formulation ready for clinical trials within five years. To accomplish this, we have four aims. In Aim 1, we will design, synthesize, and manufacture innovative new MCVs and carefully optimize the immunological conditions needed to achieve the best combination of antibody titer, affinity, specificity of response, and duration of action (i.e., therapeutic effectiveness). In Aim 2, we will test the best of these MCVs in pharmacokinetic and behavioral studies designed to select MCVs that decrease penetration of (+)METH into the brain and reduce or block drug self-administration without adversely influencing withdrawal effects. In Aim 3, safety will be determined by monitoring general animal health, measuring blood chemistries, and examining animal tissues during and after chronic vaccination. In Aim 4, a data monitoring program based on data sets collected in Aims 1-3 will be developed and enacted with industry partner InterveXion Therapeutics to maximize the potential for expedient FDA approval. The decision to take an MCV candidate to the FDA will be made in collaboration with external advisors and NIDA, then our ongoing programmatic approach will facilitate rapid transition through clinical testing, including IND application. Achieving our goal will address the major public health problem of (+)METH dependence by blocking or reducing its effects even under challenges of binge and relapse. [unreadable] [unreadable] [unreadable]